In the US civilian population, each year, approximately 500,000 patients with burns present to emergency departments. Of 40,000 annual hospital admissions, 25,000 burn victims are admitted to specialized burn centers. Average time between burn injury and arrival at a hospital, in the United States, is approximately four hours. Progressive extension of burns can have a devastating effect. Over the course of a few days to one week deep partial-thickness burns can become full-thickness burns, which in the short term, leads to increased tissue loss, longer healing time, excess morbidity and mortality. In the long term, increased scarring, wound contractures and poor quality of life become major issues. While the exact mechanism(s) leading to conversion of the zone of ischemia to full-blown necrosis is unclear, several processes, including oxidant and cytokine stress resulting from inflammation as well as ischemia/reperfusion, probably play a role. Therapies to improve blood flow, such as non-steroidal anti-inflammatory agents (NSAIDS) and anti-coagulants (heparin) have not shown substantial benefit in preventing burn injury progression. Hence therapy to limit burn injury progression is an unmet need.
There is evidence that fibronectin (FN) is involved in many biological processes including tissue repair, embryogenesis, cell migration, wound repair, and cell adhesion. There are two primary forms of fibronectin. The first is an insoluble glycoprotein dimer that serves as a linker in the extracellular matrix (ECM), and the second is a soluble disulfide-linked dimer found in plasma. The ECM form of fibronectin is expressed by fibroblasts, chondrocytes, endothelial cells, macrophages and certain epithelial cells. The plasma form of fibronectin is expressed by hepatocytes. Fibronectin can serve as a general cell adhesion molecule by anchoring cells to collagen or to proteoglycan substrates. Fibronectin can also play a role in organizing cellular interactions by binding to components of the ECM and to membrane-bound fibronectin receptors on cell surfaces. Forms of fibronectin are found in vertebrates, including mammals, birds, amphibians, fish, and reptiles.
FN, a 500 kDa glycoprotein, circulates in the blood and is produced and deposited by tissue cells in the provisional extracellular matrix (ECM) during tissue formation. As a critical component of the provisional ECM, FN plays a vital role in embryogenesis, morphogenesis and wound healing but is deficient in burn patients' wounds and blood. FN is known to be degraded in burn wound fluids by the endopeptidase neutrophil elastase. See Grinnell, et al, Identification of Neutrophil Elastase as the Proteinase in Burn Wound Fluid Responsible for Degradation of Fibronectin, J Invest. Dermatology, 1994, 103(2):155-61.
Previously disclosed peptide “P12” is 14-residue peptide that is cryptic within the immunoglobulin sandwich type of β-pleated sheet of fibronectin's (FN) first type III repeat (FNIII1). Unlike FN, P12 in solution promotes mesenchymal cell growth, proliferation and migration intrinsically and synergistically with a variety of growth factors, especially platelet-derived growth factor-BB (PDGF-BB). Furthermore, P12 protects adult human dermal fibroblasts (AHDF) from cell death induced by oxidative and cytokine stress and/or nutrient withdrawal in the presence of PDGF-BB. P12 also limits burn injury progression in rat and porcine burn models and mitigates scarring in a vertical burn injury progression pig model. See, e.g., PCT/US2006/038778; U.S. Pat. No. 8,759,300; Lin, et al, Fibronectin peptides that bind PDGF-BB enhance survival of cells and tissue under stress, J Invest Dermatol. 2014 April; 134(4): 1119-1127; and Asif, et al., Blood Vessel Occlusion in Peri-burn Tissue is Secondary to Erythrocyte Aggregation and Mitigated by a Fibronectin-derived Peptide that Limits Burn Injury Progression, Wound Rep Reg (2016) 24 501-513. In particular, the fragment of fibronectin PSHISKYILRWRPK SEQ ID NO:1, or “P12”, and a cyclized version of the polypeptide PSHISKYILRWRPK SEQ ID NO:2, or “cP12”, is disclosed U.S. Pat. No. 8,759,300, Lin, et al., and Asif, et al. as being useful for the treatment of wounds, particularly the treatment of burns. U.S. Pat. No. 8,759,300 is hereby incorporated, herein, in its entirety.
Citation of a reference in this section is not to be interpreted as an admission that the reference is prior art under 35 U.S.C. § 102 and/or 103.